Rationale and design of a community-based double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica

Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, Torre La Sabana, 300 Oeste del ICE, Piso 7, Sabana Norte, San José, Costa Rica.
Vaccine (Impact Factor: 3.62). 09/2008; 26(37):4795-808. DOI: 10.1016/j.vaccine.2008.07.002
Source: PubMed


We report the rationale, design, methods and details of participation of a community-based, double-blind, randomized clinical trial of an HPV 16 and 18 vaccine conducted in two provinces of Costa Rica to investigate the efficacy and population impact of the vaccine in the prevention of cervical cancer precursors. More than 24,000 women between 18 and 25 years of age were invited to participate and pre-screened for eligibility, with recruitment of 7466 women (30% of those pre-screened, 59% of those eligible) who were randomized to receive 3 doses of the HPV vaccine or hepatitis A vaccine as control. A complex protocol of data and specimen collection was applied, including an interview, pelvic exam for sexually active women, blood for serology and cell-mediated immunity, cervical secretions for local immunity and cells for HPV, Chlamydia trachomatis and gonorrhea testing. Eighty percent of the women received three doses, 12.4% two doses and 7.4% one dose. At visits, compliance with data and specimen collection was close to 100%. Baseline characteristics and age-specific prevalence of HPV and cervical neoplasia are reported. Overall prevalence of HPV was high (50%), with 8.3% of women having HPV 16 and 3.2% HPV 18. LSIL was detected in 12.7% of women at baseline and HSIL in 1.9%. Prevalence of Chlamydia was 14.2%. There was very good agreement in HPV detection between clinician-collected and self- collected specimens (89.4% agreement for all types, kappa 0.59). Follow up will continue with yearly or more frequent examinations for at least 4 years for each participant.

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    • "The primary outcome for efficacy was defined as histopathologically confirmed CIN2+ associated with HPV-16/18 cervical infection detected by PCR in the cervical cytology specimen that led to colposcopy referral. Final histological diagnosis was defined based on blinded review by a Costa Rican and a US pathologist, with blinded review by a third pathologist in instances where the first two reviewers disagreed [11]. In secondary efficacy analyses, we evaluated histopathologically confirmed CIN2+ associated with non-HPV-16/18 and any oncogenic HPV cervical infections (HPV types 16,18,31,33,35,39,45,51,52,56,58,59,68/73) detected by PCR in the cervical cytology specimen that led to colposcopy referral, and time to incident infection with HPV-16/18 cervical infections. "
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    ABSTRACT: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated.
    Vaccine 09/2014; 32(39). DOI:10.1016/j.vaccine.2014.06.038 · 3.62 Impact Factor
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    • "Our study population was sampled from the control (HPV-unvaccinated) arm of the Costa Rica Vaccine Trial (CVT), which has been described in detail [28]. The control arm comprised 3,736 women aged 18–25 in Guanacaste, Costa Rica who were followed annually for 4 years, providing a serum sample at each visit. "
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    ABSTRACT: Several assays are used to measure type-specific serological responses to human papillomavirus (HPV), including the bead-based glutathione S-transferase (GST)-L1 multiplex serology assay and virus-like particle (VLP)-based ELISA. We evaluated the high-throughput GST-L1, which is increasingly used in epidemiologic research, as a measure of cumulative HPV infection and future immune protection among HPV-unvaccinated women. We tested enrollment sera from participants in the control arm of the Costa Rica Vaccine Trial (n = 488) for HPV16 and HPV18 using GST-L1, VLP-ELISA, and two assays that measure neutralizing antibodies (cLIA and SEAP-NA). With statistical adjustment for sampling, we compared GST-L1 serostatus to established HPV seropositivity correlates and incident cervical HPV infection using odds ratios. We further compared GST-L1 to VLP-ELISA using pair-wise agreement statistics and by defining alternate assay cutoffs. Odds of HPV16 GST-L1 seropositivity increased with enrollment age (OR = 1.20 per year, 95%CI 1.03-1.40) and lifetime number of sexual partners (OR = 2.06 per partner, 95%CI 1.49-2.83), with similar results for HPV18. GST-L1 seropositivity did not indicate protection from incident infection over 4 years of follow-up (HPV16 adjusted OR = 1.72, 95%CI 0.95-3.13; HPV18 adjusted OR = 0.38, 95%CI 0.12-1.23). Seroprevalence by GST-L1 (HPV16 and HPV18, respectively) was 5.0% and 5.2%, compared to 19.4% and 23.8% by VLP-ELISA, giving positive agreement of 39.2% and 20.8%. Lowering GST-L1 seropositivity cutoffs improved GST-L1/VLP-ELISA positive agreement to 68.6% (HPV16) and 61.5% (HPV18). Our data support GST-L1 as a marker of cumulative HPV infection, but not immune protection. At lower seropositivity cutoffs, GST-L1 better approximates VLP-ELISA.
    BMC Infectious Diseases 03/2014; 14(1):120. DOI:10.1186/1471-2334-14-120 · 2.61 Impact Factor
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    • "The study population consisted of all 3,739 women participating in the control group of the Costa Rican Vaccine Trial (CVT; NCT00128661)). Study design and procedures have been described elsewhere [8]. Briefly, CVT is a community-based, double-blind randomized phase III trial aimed at evaluating the efficacy of HPV 16/18 bivalent vaccine in preventing cervical precancers. "
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    ABSTRACT: High risk human papillomaviruses (HR-HPV) are known to be extremely common, sexually transmitted infections, but more information is needed regarding the absolute risks of type-specific HR-HPV infections in the years following sexual debut. We conducted a survival analysis of 3,737 women aged 18--25 from the control group of the Costa Rican Vaccine trial to determine the absolute risks of HR-HPV infections at 12 months, 24 months, and end of follow-up (average of 50.7 months). To corroborate determinants of infection, we used Cox proportional hazards methods to assess associations between demographics and sexual risk behaviors and incident HR-HPV. Cumulative incidence for HR-HPV infections was 51.3% at the end of the study period. The most common incident types were HPV52 (15.4%), HPV51 (13.6%), and HPV16 (12.4%). Type-specific cumulative incidence corresponded closely with type-specific prevalences, except that HPV16 was more prevalent than predicted by incidence, suggesting greater persistence. The strongest predictors of incident HR-HPV infections as a group in a multivariate analysis were the expected correlates of sexual behavior of the woman and her partner, such as being single (HR 1.6, 95% CI 1.4-1.8) or divorced/widowed (HR: 2.1, 95% CI: 1.7-2.7), having multiple HPV infections at enrollment (HR: 1.5, 95% CI: 1.3-1.7), and current smoking (HR: 1.2, 95% CI: 1.0-1.3). In women who reported being having only one lifetime sexual partner (being in a monogamous relationship), the strongest predictors of HR-HPV included not living with sex partner (HR: 2.1, 95% CI 1.7-2.5) and age of sex partner (HR: 1.4, 95% CI: 1.0-1.8). We confirm the extremely high incidence of HR-HPV in young women, emphasizing the importance of vaccinating young girls before sexual debut.
    BMC Infectious Diseases 07/2013; 13(1):308. DOI:10.1186/1471-2334-13-308 · 2.61 Impact Factor
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